"MIC is the lowest concentration of an antibacterial agent expressed in mg/L (μg/mL) which, under strictly controlled in vitro conditions, completely prevents visible growth of the test strain of an organism [2]" Source
This is the persistence of antibiotic effect observed long after the serum concentration has fallen below the MIC.
- Macrolides do have a strong post antibiotic effect but they are time-dependent killing antibiotics.
Mnemonic: macrolides -> sequestered in macrophages.
⭐
| Linezolid | Daptomycin | Vancomycin and Teicoplanin |
- Those which kill bacteria most effectively at some specific event which occurs intermittently, eg. classically when the bacteria are about to divide.
- Bactericidal activity continues only as long as the concentration is above MIC! Source
Examples of this include β-lactams, carbapenems, monobactams, linezolid, linocosamides like clindamycin, and macrolides like erythromycin and vancomycin.Source
- Seen with antibiotic which disable some crucial step in bacterial metabolism.
- Seen with DNA synthesis inhibitors (fluoroquinolones) and protein synthesis inhibitors (aminoglycosides)
- Drugs with concentration dependent killing tend to show the post antibiotic effect.
- Mechanisms: drug remains bound to substrate, bacteria are slow to recover after antibiotic action, etc.Source
- The higher the concentration, the more bacterial are disabled.
- Longer dosing intervals can be used.
- Longer dosing intervals reduced average plasma concentration (AUC) and mimimize side effects.
- Effort and exercise tolerance are preserved but ⭐**spasm can be triggered by exercise** during 'hot phase' of the condition.
- Beta blockers are contraindicated as they can worse spasm.
- Management is with dihydropyridine calcium channel blocker (felodipine, amlodipine)
- Anti Hu - painful paraneoplastic neuropathy. Associated with small cell lung cancer. (Hu - Hurt -> painful neuropathy) And also paraneoplastic limbic encephalopathy
- Somatostain itself has a short half life lasting minutes. Octreotide and other analogs have been made to have longer half lives (upto 2 hours) Source
The "G" hormones are more sensitive
⭐Acromegaly
- Decreased secretion of other pituitary hormones -> ⭐most commonly gonadotrophins
- Menstrual dysfunction, vaginal atrophy, galactrorrhea
- Hyperprolactinaemia - either increased [[#Prolactin]] secretion from the somatotroph adenoma or inhbition of dopaminergic inhibition -> causes galactrorrhea
- Soft tissue overgrowth - large tongue (macroglossia), carpal tunnel syndrome + the other classic ones
- heart: cardiomyopathy and LVH with diastolic dysfunction and arrhythmias - secondary to hypertension
- Hypertension: GH-IGF-I excess -> enhanced sodium- and water retention -> expansion of plasma volume and increased systemic vascular resistance. Source
- Hyperinsulinaemia may also stimulate salt and water retention Source
- colonic neoplasms
- octreotide - somatostatin analog
- pegvisomant - prevents dimerization of IGF-1 receptors (i.e a receptor antagonist), very effective
- Features of prolactinomas which help to identify a prolactinomas as the cause for hyperprolactinaemia -->
- lactotroph adenomas are efficient: so even microadenomas can produce a clinically significant amount of prolactin without causing pressure symptoms.
Part of a constellation of conditions including fibromyalgia, chronic fatigue syndrome.
2. altered bowel habits - either diarrhoea or constipation +/- intervals of normal bowel habits.
[!INFO]
[!NOTE] ROME IV criteria
?symptoms can worse in the premenstrual period.
+ **Mebeverine** (antispasmodic)
+ Explantion of symptoms, **CBT**, hypnotherapy,
+ **SSRI** -Constipation predomimant IBS , TCA -diarrhoea predominant IBS
- fever, hepatosplenomegaly, rash, neurologic findings, and pancytopenia can occur.
- Macrophage activation syndrome (MAS) refers to a form of HLH that occurs primarily in patients with juvenile idiopathic arthritis or other rheumatologic diseases
- HLH patients rarely have prominent lymphadenopathy;
- When to suspect: Any adult with daily or twice daily fever spikes with evanescent, salmon pink, non pruritic rash (which disappears with settling fever)
- MAS is the leading cause of death for patients with AOSD
| DD | Distinguishing feature | |
| ------------------------ | ------------------------------------------------------------------------------------- | --- |
| Sepsis/inf. endocarditis | They will show immature neutrophiles, blood cultures will be positive | |
| Viral infections | Usually self limiting, timing of rash identifies AOSD | |
| Lymphoma | Lymph node biopsy shows benign hyperplasia in AOSD; required immunohistochemistry | |
| Other rheumatic diseases | See below | |
- Characteristic feature: Fusion of wrist joints
- ? Initial destructive arthritis progresses to severe destructive arthritis.
- There is non-erosive narrowing of CMC joints.
| AOSD Alone | AOSD + MAS |
| -------------------- | --------------------------------------------------------------------------------- |
| | Lymphadenopathy, weight loss, hepatomegaly, splenomegaly, neurologic symptoms |
| ⬆ferritin | ⬆⬆ferritin |
| ⬆ transaminitis | ⬆⬆ transaminitis |
| normal TGL | ⬆⬆ Serum TGL |
| Only anaemia | cytopenias |
| ESR can be normal! | ESR can be normal! (due to low or normal haptoglobin and fibrinogen) |
| | BM biopsy shows haemophagocytosis |
- The mec gene was probably acquired from coagulase negative staphylococci.
- Lewy bodies (neuronal inclusions made of ⭐alpha-synuclein and ⭐ubiquitin) seen first in medulla -> pons -> substantia nigra.
| Lewy Body | Pale substantia nigra |
| ----------------------------- | -------------------------------------- |
| 
| 
|
| Main motor symptoms | Others | |
| --------------------------- | --------------------------------------- | --- |
| Tremmor, akinesia, ridigity | Writing becomes smaller, mask like face | * |
|Pergolide, Lisuride, Cabergoline, Bromocriptine | pramipexole, ropinirole, rotigotine |
| 
| |
⭐🚩None of the drugs in Parkinson's alter disease progression.
[!INFO] motor complications of treatment
- End of dose wearing off effect
- Choreiform movements / dyskinesias
- They occur after 2 years of starting levodopa treatment. More with levodopa (LID's - levodopa induced dyskinesias) (compared to dopamine agonists) because levodopa has short half life and concentrations fluctuate.
- On off phenomena
- Orthostatic hypotension
- A late side effect. Managed by reducing drug doses.
- Another late side effect. Manage by reducing drug doses.
- Impulse control disorders (ICDs)
- Most commonly associated with dopamine agonists.
- Sudden withdrawal can cause parkinsonism-hyperpyrexia syndrome - basically, neuroleptic malignant syndrome occuring in the context of antiparkinson drug withdrawal or when switching antiparkinson's agents.
- ⭐Levodopa or Dopamine agonists should not be stopped abruptly.
- Abrupt Discontinuation of anticholinergics can cause acute exacerbation of Parkinsonism.
| Effect | Levodopa
| Dopamine agonists
| MAO‑B inhibitors |
| ------------------------------ | -------------------------------------- | ---------------------------------------------- | ---------------------------------------------- |
| Motor symptoms | More improvement in motor symptoms | Less improvement in motor symptoms | Less improvement in motor symptoms |
| Activities of daily living | More improvement in ADL | Less improvement in activities of daily living | Less improvement in activities of daily living |
| Motor complications | More motor complications | Fewer motor complications | Fewer motor complications |
| Adverse events | Fewer specified adverse events* | ⚠️More specified adverse events* | Fewer specified adverse events* |
| Effect | Dopamine agonists | MAO‑B inhibitors | COMT inhibitors | Amantadine |
| Off time | More off‑time reduction | Off‑time reduction | Off‑time reduction | No studies reporting this outcome |
| Adverse events | Intermediate risk of adverse events | Fewer adverse events | More adverse events | No studies reporting this outcome |
| Hallucinations | More risk of hallucinations | Lower risk of hallucinations | Lower risk of hallucinations | No studies reporting this outcome |
| Amantadine | ⭐Enhances dopamine release | Modest effect - used in advanced disease to improve diskinesia | |
| Antimuscarinics (orphenadrine)
(Benzhexol) | | used to reduce tremmor in younger patients as confusion can occur in older patients | dry mouth, blurred vision, constipation, nausea, urinary retention, impaired sweating, and tachycardia |
- Donapezil, Rivastigmine, Galantamine cholinesterase inhibitors can be used in Parkinson's dementia.
- *Nerve growth factor* : **a key element of inflammatory pain**. It induces hyperalgesia by up-regulating the transcription of genes encoding receptors, ion channels, and neuropeptides. [Source](https://www.sciencedirect.com/science/article/pii/S0021925820756589)
- So platelet activity returns only when ⭐new ones are formed in 7-10 days.
- Side effects: High doses can cause dizziness, deafness, and tinnitus.
- Toxicity: Decouples oxidative phosphorylation leading to excessive CO2 production and respiratory alkalosis due to direct stimulation of respiratory center. Even higher doses may cause a high anion gap metabolic acidosis.
- Low doses (typically 75 to 81 mg/day) are sufficient to irreversibly acetylate serine 530 of cyclooxygenase (COX)-1. This effect inhibits platelet generation of thromboxane A2, resulting in an antithrombotic effect
- Intermediate doses (650 mg to 4 g/day) inhibit COX-1 and COX-2, blocking prostaglandin (PG) production, and have analgesic and antipyretic effects.
- High doses (between 4 and 8 g/day) are effective as antiinflammatory agents in rheumatic disorders; the mechanism(s) of action at these high doses may include both PG-dependent (particularly COX-2-dependent PGE2) and independent effects. However, the usefulness of aspirin at these high doses is limited by toxicity, including tinnitus, hearing loss, and gastric intolerance.
- Mechanism: inhibits phosphodiesterase and adenosine deaminase which cause accumulation of of cAMP and adenosine. The rise of cAMP ⭐inhibits thromboxane A2 synthesis. Also causes coronary vasodilation.
- Unlike aspirin, it ⭐does not increase bleeding risk.
- Mnemonic: tiggers bounce -> therefore, ticagrelor is reversible
- They inhibit adenosine mediated platelet ⭐aggregation.
- Prasugrel is not used after ischemic stroke / TIA due to increased bleeding risk.
- Abciximab is a monoclonal antibody which does this; ⭐Only one dose can be given before the body forms effective antibodies to it.
- Abciximab was also shown to have ⭐increased bleeding tendency following stroke so it's not used for this purpose.
- Tirofiban and eptifibatide are also IIb/IIIa blockers which are given IV to reduce early events in ACS.
| Beta lactams, Cephalosporin |
Inhibit cell wall synthesis |
|
|
⭐ |
|
- Fusidic acid
- and lincosamide - clindamycin.
- macrolides - erythromycin, azithromycin , clarithromycin
- aminoglycoside
- tetracycines
- chloramphenicol
- This resulted in MRSA. See [[Bacterial pathogens#MRSA]]
Penicillin - is secreted by renal tubules to clearance is > than GFR.
- Focal onset *impaired awareness* seizures: aka ⭐*complex partial* seizures.
- Bioequivalence indicates that different drug products, when given to the same patient in the same dosage regimen, result in equivalent concentrations of drug in plasma and tissues.
- Therapeutic equivalence indicates that drug products, when given to the same patient in the same dosage regimen, have the same therapeutic and adverse effects.
""Drugs are considered bioequivalent if the extents and rates of absorption of drug from them are so similar that there is likely no clinically important difference between their effects""
- Bioequivalence rests on the assumption that the measured drug concentration is related to its clinical effect.
- i.e is it assumed that if the AUC is the same, the the clinical effect is the same.
- Source